Andy Grove's Last Stand

The former Intel chief, now battling Parkinson's, is on a crusade to speed progress in treating the disease. Can he make a difference?

Andy Grove noticed an occasional tremor in the index finger of his right hand. it was 1999, when Grove was 63 and had just stepped down as the chief executive of chipmaker
Intel
. His physician dismissed the twitchy digit. A year later another doctor nudged him to see a specialist in movement disorders. "She had me close my eyes, put my head in my hands, and count backwards from 100 by sevens," says Grove.

The doctor told him he had Parkinson's disease. "It didn't mean much to me," he recalls. "I didn't know anyone with Parkinson's." His younger daughter, who had accompanied him to the appointment, nearly fainted. A physical therapist, she had worked with Parkinson's patients who were homebound and unable to feed themselves.

Andrew Grove, a man who survived the Nazis, the Communists, scarlet fever, prostate cancer and Bill Gates to run what was briefly one of the world's five most valuable companies, is saddled with a disease that will eventually rob him of control over his body. But before it debilitates him, Grove is going to fight. Over the past eight years Grove has immersed himself in the minutiae of the disease and has used his money and his stature to agitate for more and faster research on the neurology of Parkinson's. "You can't go close to this and not get angry," says Grove. "There are so many people working so hard and achieving so little."

Grove, who is worth an estimated $400 million, has committed $22 million to Parkinson's research and pledged a $40 million bequest to the Michael J. Fox Foundation for Parkinson's Research, to which he is an adviser. "There's 500,000 Andy Groves out there, and 500,000 Michael J. Fox's. Whatever is good for me is going to be good for a large constituency," he says.

Other rich and famous folk have been inspired by their own medical conditions, or those of a child or spouse, to move mountains, usually without much success. Actor Christopher Reeve put the spotlight on spinal cord injuries after he was paralyzed in 1995 in a riding accident. Reeve died in 2004, and there is still no cure for spinal cord injuries. CBS News anchor Katie Couric inspired more people get colonoscopies following the death of her husband from colorectal cancer in 1998. Still, only 40% of adults aged 50 to 64 have had a colonoscopy.

Grove is by training a scientist and a boss. With the research he funds, Grove demands regular updates, challenges assumptions and asks for new experiments. His goals are characteristically both pragmatic and audacious: to push the research and set an example of more goal-oriented projects that, even after he's gone, others can continue.

Slowly, he is changing--or at least provoking--minds inside the biomedical establishment. In early November, speaking to a room of several hundred people at the annual Society for Neuroscience conference in San Diego, Grove roundly criticized research funding at the National Institutes of Health, the unwillingness of researchers to share data and the lack of urgency in translating basic science into treatments that can help people. "What is needed is a cultural revolution that values curiosity, follow-through and a problem-solving orientation and also puts the data being generated in full view, scrutinizable by all," Grove said during the speech.

Some people would say "amen" to all that. Some wouldn't. "The human body is a lot more complex than silicon," said a professor of biomedical engineering and radiology at Columbia University after Grove's speech. Derek Lowe, a veteran pharma researcher with a Ph.D. in organic chemistry, called Grove "Rich, Famous, Smart and Wrong" in his blog.

Grove, 71, coined the metaphor "strategic inflection point" to describe the moment when an industry or company changes its trajectory. Is it time for an inflection point in neurological research?

Grove has had as many inflection points as one life could stand. He fled his native Hungary in 1956 to embark on a career in the U.S. After earning a Ph.D. in chemical engineering, he abandoned the field for the more promising emerging area of electronics. He was employee number one at Intel. In 1984 he and Intel cofounder Gordon Moore decided to abandon the memory chip business that gave the company its start for what became a dizzyingly successful string of microprocessors. He also morphed personally--from a drill sergeant fab manager to industry visionary.

In 1995 Grove was diagnosed with prostate cancer. He set about meticulously researching various treatment options and the survival odds of each one before undergoing a relatively new radiation therapy. So far the cancer has not reappeared. He was happy with the treatment but not so happy with what he learned about the slow pace of medical research on the disease. He used his case to draw attention to the matter.

So, too, with Parkinson's. The drugs approved to treat it address only the symptoms: rigid muscles, loss of balance, slow or uncontrollable movement. Eventually, patients reach a point at which those drugs stop working. There are no blood or urine markers for the disease; neurologists diagnose it by asking questions and observing.

Parkinson's affects at least 1 million Americans and another 5 million people around the world. It results from a loss of cells in the brain that produce a chemical messenger called dopamine, which coordinates movement. Parkinson's itself doesn't kill people, but patients with advanced cases die of complications such as injuries from falling and pneumonia. Some with it live for decades, but their quality of life can deteriorate dramatically. Many suffer from exhaustion and depression.

Grove initially shared his diagnosis with only the Intel board and a few colleagues and friends; it became known to the public only in a 2006 biography by Richard Tedlow. "I did not want to become a poster child for yet another disease. I was so sick of being the first and last contact for prostate cancer," he says. "Cancer you don't see. This thing [Parkinson's] makes me look like an old man. And I'm a vain guy."

After reading up on Parkinson's, Grove figured he had 15 years to take action before it weakened him so much that he couldn't promote a scientific assault on the disease. He held off taking any medications because his symptoms were minimal and he believed the drugs' beneficial effects would dwindle with long use. Since studies show that caffeine consumption is linked to a lower incidence of the disease, he doubled his coffee drinking to two mugs a day. And he began exercising for an hour and a half a day--yoga, aerobics, kickboxing. "I have become a zealot," he says, showing off a video of a kickboxing session with his trainer. Studies in animals show exercise keeps brains healthier; anecdotal evidence in humans supports the theory.

In 2001 Grove and a doctor friend at Stanford University sent a letter to NIH director Elias Zerhouni with advice on how to organize NIH research grants around different diseases, including Parkinson's. "I put my heart and soul into that letter and got no answer," says Grove. It was around then he began to get angry about the lack of urgency in Parkinson's research.

Grove spent 35 years in a company that depended entirely on its ability to develop a newer, faster version of its previous product every year. "In my experience people who are getting a chip ready for production are absolutely absorbed in it and driven to meet the deadline." Medical researchers, in his view, lack an urgency to translate basic research into practical tools. The NIH spends $200 million a year on Parkinson's. Yet the mainstay drug, levadopa, which stimulates the brain to produce more dopamine, is 40 years old and provides only symptomatic relief.

Shortly after he was diagnosed, Grove asked his old friend C. Barr Taylor, a professor of psychiatry at Stanford University Medical Center, to become an adviser to a new Parkinson's arm he was creating within his personal foundation. Initially Grove was enthusiastic about the potential of embryonic stem cells as a treatment. He gave $5 million to ucsf to further stem cell research, at a time when such research was getting only a few million dollars a year. In 2002 he joined the Fox Foundation in funding eight other stem cell labs.

By 2003 researchers he had funded were able to turn embryonic stem cells into dopamine-producing neurons, but once they were put into mice, the neurons either reverted to embryonic stem cells or stopped producing dopamine. A second round of stem cell grants issued by Grove and the Fox Foundation in 2004 resulted in further dead ends, including an experiment in which some dopamine-producing cells developed tumors.

Grove's condition was growing worse. In 2004 the tremor forced him to switch from wearing contact lenses to eyeglasses. He used voice recognition software instead of typing on his computer. His face took on a masklike quality as the facial muscles became rigid. At Intel's February 2005 marketing conference in Anaheim, Calif. Grove realized shortly before a speech that he would be unable to grasp the pages and turn them. Ten minutes before the speech an assistant flattened all the pages on the lectern, according to Tedlow's biography. Several months later Grove began taking the minimum dose of levadopa. It didn't take long before people noticed a difference. Grove remembers Intel Chairman Craig Barrett telling him how spry he looked.

One of Grove's frustrations is the standard test neurologists use to measure a patient's level of severity of Parkinson's. The test, the Uniform Parkinson's Disease Rating Scale, is subjective. Doctors must make judgments during a 15-minute appointment about a patient's ability to speak, move and walk. But symptoms vary widely from day to day and even hour to hour, so the snapshot taken by the physician may not be very representative. It's about as far from the ordered, repeatable world of chip-manufacturing as you can get. "updrs is a piece of crap," Grove scoffs.

In May 2005, when he was stepping down as chairman of Intel, Grove asked Eric Dishman, the head of research at what would later become Intel's digital health division, if he could develop a machine that would objectively measure whether a patient was getting worse. Dishman incorporated two tests that measure the strength of a patient's speech with a recording chip, and three others--a peg board, two piano keys and videogame-type buttons--that measure reaction time and speed of movement. "All the measurement that was put in this box has existed for years. No one has applied them for measuring progression," sighs Grove.

Grove put in $2 million and Intel contributed around $1 million worth of engineering to create and test the prototype, known as the At Home Box. If it works, it could be used in trials of drugs. Grove is reluctant to criticize his alma mater, but he's frustrated with the fact that it's taken Intel this long to publish the data from the trial of the At Home Box.

A constant source of tension for Grove is what he perceives to be a reluctance by the medical research establishment to go back and ask why things fail. Grove proudly remembers that Intel employees intensely focused on learning from failure. Not only did that prevent the repeat of a failure, but it sometimes led to valuable insights on, say, how to make a manufacturing process more efficient.

Drug development is different. In 2004 biotech firm
Amgen
began trials of a Parkinson's drug called glial cell line-derived neurotrophic factor, or GDNF. The drug is a protein that has been linked to promoting survival and growth of neurons. In an earlier trial five patients in the U.K. had undergone a surgery in which a tiny catheter implanted in their brains continuously delivered GDNF from a pump inserted in the stomach (the pump is refilled with a needle through the skin). They appeared to be getting better. But in the Amgen trial patients improved on average a disappointing 20%. After studies in primates showed high levels of toxicity from GDNF, Amgen halted further human trials.

But at least two researchers still working on GDNF say Amgen's problem was the way the drug was delivered. Grove looked at the data and noticed that one patient improved 80%. "Who was that person and what do we know about him?" he asks. Nothing, because no one bothered to follow up. Steven Gill, the British neurosurgeon who ran that first GDNF infusion trial, believes the cause of the toxicity was the improper infusion of the drug into the monkeys' brains. Many people with Parkinson's were crushed by Amgen's decision to stop the GDNF trial. Ten trial participants sued unsuccessfully to keep getting the drug, because they believed it was helping them.

Amgen may not have examined why GDNF failed, but
Pfizer
has been learning from its failed clinical trials for decades. Four years ago it formalized a division to analyze failed trials. "It's acknowledged that success in this industry is linked to understanding failure. We aim to get good at predicting dead ends before we start a clinical trial," says Dr. Liam Ratcliffe, head of Pfizer's failure analysis division.

Treatments for neurodegenerative diseases like Parkinson's lag far behind those for cancer for a couple of daunting reasons. First, there's a lot more money invested in cancer research. And spinal cord and brain cells don't regenerate; scientists can't grow them in a dish for convenient testing as they can with a tissue of a cancerous breast or a lymph node, says Jeffrey Rothstein, a professor of neurology at Johns Hopkins. Another hurdle: figuring out how to get drugs into the brain. Brain blood vessels have a membrane structure insulating them from chemicals circulating in the blood. It irks Grove that so little research is being done on the blood-brain barrier or on other ways of delivering drugs to the brain. "Each of you can spend a lifetime developing a bioactive drug. If you can't get them repeatedly and reproducibly to the target area, you have wasted a career," Grove told the researchers at the neuroscience conference in November.

Grove has funded several researchers trying to inject GDNF into the brain. One, Krystof Bankiewicz at ucsf, credits funding from Grove with drastically speeding up his research. "My lab is developing a whole treatment strategy. We hope to have it in [clinical trials] in less than two years," says Bankiewicz. With typical NIH grants, it would take him two years just to get the funding. "What [Grove] is funding in my lab has a very, very good chance of really working." Bankiewicz adds that Grove has made him more organized. "He forces me to be a better manager."

In late November Grove began trying to persuade a large medical company with which he has no affiliation to license the GDNF program from Amgen, in order to revive it. At press time no deal had been signed, but Grove is optimistic.

The chief executive in Grove lives on without the title. He likes to order around people who don't even work for him--all in the name of progress on Parkinson's. At a meeting with Michael Weiner, an expert on brain imaging and a professor at UCSF, Grove tells Weiner what he should talk about at a January meeting of experts on growth factors that Grove has organized with the Michael J. Fox Foundation. Then he urges Weiner's colleague, Norbert Schuff, to include a subset of patients not yet on medication in a brain-imaging study Schuff is doing. Both men nod to his requests. Grove also delves into the research he funds as if it were his own, questioning results, tracking down related research and proposing new experiments. "I haven't done this in decades. I feel like I'm back in graduate school," Grove beams.

Yet Grove is all too aware these days that he has to seize each day with determination. During a visit to the Parkinson's Institute in Sunnyvale, Calif., Grove directs a visitor's attention to an older man, aided by a three-pronged cane, slowly shuffling from the parking lot into the building. Inside in the waiting room one woman's hand is completely hidden by the severe crook of her wrist. For these patients, the ability to walk at all may not last much longer.